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Lecture

Section 6

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Department
Biology
Course
Biology 2382B
Professor
Sashko Damjanovski
Semester
Winter

Description
SECTION 6 Membrane Proteins • With the exception of needing phospholipids to form semi- permeable closed compartments, membrane proteins carry out the biological functions of membranes. • Three types: 1. Integral 2. Lipid-linked 3. Peripheral • All are asymmetric Integral Membrane Proteins • Asymmetric – specifically oriented • Three distinct “domains”: o Cytoplasmic (hydrophilic) o Transmembrane (hydrophobic) o Exoplasmic (hydrophilic) • Transmembrane domain – hydrophobic secondary or tertiary structures that span the lipid bilayer • Different configurations – most common are the αhelices and β barrels • α helices (approx. 20-25 amino acids) • Arg and Lys (chargedAAs) near cytosolic side interact with polar head groups • Mostly glycosylated in exoplasmic domain (extracellular area) Lipid-Linked Proteins • Proteins that are linked to existing phospholipids in the bilayer • Proteins anchored to membrane by lipophilic adduct o Acylation of Gly residue of protein  Need N-terminal glycine  Linked to cytosolic side of the membrane o Prenylation of Cys residue of protein  Need C-terminal cysteine or cysteine close to C-terminal  Linked to cytosolic side of the membrane o Glycosylphosphatidylinositol (GPI) anchor  Needs phosphatidylinositol (one of the phospholipids)  Always on the exterior surface  With phosphatidylinositol, certain proteins can be linked  Recall: N-CAM is integral membrane protein – has all three domains and is involved in cell adhesion  But if N-CAM only has a GPI anchor, it can still be involved in cell adhesion, but it does not have cytoplasmic domain • Polypeptide chain (protein) does not enter bilayer • Has lateral mobility in membrane • Acylation attaches through N-terminal Gly residue • Prenylation attaches Cys residue at or near C terminus Peripheral Proteins • “Attached” through non-covalent interaction to either integral membrane proteins or lipid-linked proteins which are already linked to and part of the plasma membrane, through: o Ionic interactions, hydrogen bonds o Protein-protein interactions o van der Waals forces • Cytoskeletal filaments can associate with bilayer through peripheral proteins, as can ECM components o Depending on whether they are bound to integral membrane proteins or lipid-linked proteins Insertion of Proteins into Membranes • Need to know orientations of the different types of proteins – type I, II, III, and IV (where C-terminal and N-terminal are located – cytosol or exoplasmic space) • All translation is occurring in the cytosol, to get the protein to the membrane it needs a signal • The N-terminal signal sequence is a type of topogenic sequence, form a specific type of shape (topology) • Another type of signal sequence is the SA sequence – signal = go to the ER and the STAsequence – stop transferring to the ER • N-terminal (cleaved) signal sequence • Stop-transfer/membrane anchor sequence (STA) • Signal-anchor - Internal (uncleaved) sequence (SA) • Hydrophobic C-terminus • Tail anchored proteins o Requires Get3 recognition of hydrophobic C-terminal tail, membrane embedded Get1 and 2, andATP hydrolysis o With tail anchored proteins, N-terminal domain is always in the cytosol and the C-terminal domain is always in the ER membrane Insertion of tail-anchored proteins: for C-terminal tail anchored proteins the hydrophobic C-terminus is not available for membrane insertion until protein synthesis is complete and the protein has been released from the ribosome. Step 1: Get3 in anATP-bound state binds to the hydrophobic C-terminal tail. This binding reaction is facilitated by a complex of three proteins (not shown) Step 2: The ternary complex Get3-ATP bound to the C-terminal docks onto the Get1 and Get2 proteins, which are embedded in the ER membrane Step 3:ATP is hydrolyzed andADP is released from Get3, and at the same time, the hydrophobic C-terminal tail is released from Get3 and becomes embedded in the ER membrane Step 4: Get3 binds toATP and Get3-ATP is released from the complex of Get1 and Get2 in a soluble form, ready for another round of binding to a hydrophobic C-terminal tail. Synthesis of Type I Proteins • Have N terminal signal sequence • Have stop-transfer membrane anchor • N-terminal signal sequence signals “take me to the ER”, translation continues and the N-terminal domain goes into the ER lumen and is cleaved off o This is always luminal • Translation continues until it reaches the stop-transfer membrane anchor, which signals a stop o This is always cytoplasmic Synthesis of Type II and Type III Proteins • Have signal-anchor sequence (internal and not cleaved) • Translation starts and N-terminal domain is formed, signal-anchor sequence (transmembrane domain) o If there are positive charges on the N-terminal side, it stays in the cytosol o If there are no charged amino acids, the N-terminal domain moves to the lumen and translocation continues – results in positively charged amino acids on the C-terminal domain (a) Type II proteins Step 1:After the internal signal-anchor sequence is synthesized on a cytosolic ribosome, it is directed to the ER membrane. It becomes oriented in the translocon with its N-terminal portion toward the cytosol. This orientation is mediated by the positively charged residues. Step 2:As the chain is elongated and extruded into the lumen, the internal signal-anchor moves laterally out of the translocon and anchors the chain in the phospholipid bilayer. Step 3: Once protein synthesis is completed, the C-terminus of the polypeptide is released into the lumen and ribosomal subunits are released into the cytosol. (b) Type III proteins Step 1:Assembly is by a similar pathway to that of type II proteins except that positively charged residues on the C- terminal side of the signal-anchor sequence cause transmembrane segment to be oriented within the translocon with its C- terminal portion oriented to the cytosol and the N-terminal side of the protein in the ER lumen Steps 2, 3: Chain elongation of the C-terminal portion of the protein is completed in the cytosol, and ribosomal subunits are released • Orientation determined by positively charged amino acids (kept in cytosol) Synthesis of Type IV Proteins • Has multiple transmembrane domains, also varies in terms of whether the N-terminal domain is in the cytosol or the extracellular space or whether the C-terminal is in the cytosol or the lumen • Orientation of initial helix determined by positively charged amino acids next to signal-anchor sequence • Have alternating signal-anchor sequences and stop transfer sequences • Can have even or odd number of transmembrane domains Topogenic Sequences • Signal, whether it is a internal signal anchor or N-terminal signal anchor, signals to go (translate) to the ER • With this nomenclature, translation is always started at the N- terminal domain • Type I – one transmembrane domain that comes from STA, N-terminal domain in lumen, and C-terminal domain in the cytosol • Type II and II – SAis the transmembrane domain, what about the N-terminal domain? o If there are charges between the N-terminal domain and the SA, N- terminal domain stays in the cytosol, and thus C-terminal will be in the lumen o If there are no charges between the N-terminal domain and the SA, the N-terminal domain goes into the lumen and the rest of the protein stays cytosolic o Charges are cytosolic • Type IVAand
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